This proposal is directed toward the preparation of effective, new members of the ionophoric polyether antibiotics, a class of molecules which includes compounds with pronounced cardiovascular (inotropic) activity. We have developed a hypothesis which rationalizes the complex stereochemistry of these materials and thus relates their structure to their ion- binding activity. The basis of the hypothesis is that stereochemistry and substitution work together to rigidify the ionophore in the binding conformation to thus enhance ion affinity. If the hypothesis is correct, then it should be possible to design new, structurally related ionophores which retain the activity of the natural ionophores. To test the hypothesis, we will synthesize a series of derivatives of the natural ionophores lasalocid and monensin and measure their binding properties. Some of the derivatives are predicted by our hypothesis to be poor binders of ions ad others are predicted to be good binders. We will also synthesize totally unnatural ionophores whose ion-binding properties should resemble those of the natural polyethers and develop general methods for synthesis and study of natural and unnatural ionophores.
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